Anticonvulsant process and composition



United States Patent 3,145,142 ANTHCUNVULSANT PROCESS AND COMPQSHTKGN Peter T. Lansbury, Williamsville, Nfil, assignor to E. I.

du Pont tle Nemours and Company, Wilmington, Beth,

a corporation of Delaware No Drawing. ll iletl May (ill, 1962, Ser. No. 198,715

7 Claims. (Cl. l67-65) This invention relates to new articles of manufacture and to methods of making and using the same. More particularly, this invention relates to 1,3,5,-trimethyl-striazine-2,4,6(lH,3l-I,5H)-trione and its use as an anticonvulsant medicament for controlling convulsive seizures.

A considerable number of chemicals have been used as anti-convulsants for control or relief of various types of convulsive seizures, including epileptic seizures, and to a certain extent have met with more or less success in the control of such seizures. Unfortunately, most of the compounds which have achieved success posses undesirable side reactions which either limit their use or add further to the distress of the unfortunate user.

Many of the known compounds used as anti-convulsant medicaments cause dizziness, lethargy, and a reduction in the coordination ability of the patient, whether the patient be human or other warm blooded animal, as well as nervousness and visual disturbances. Another group of known compounds sometimes used as anti-convulsant medicaments produce incoordination, gastric distress, and similar undesirable reactions. Toxic effects of a more serious nature are common and agranulocytosis and aplastic anemia are frequently observed. It is apparent, therefore, that the need for a safe and eflicient anticonvulsant medicament has not been fully met by anticonvulsant medicaments known in the prior art.

Among the several objects of this invention, therefore, can be noted the provision of new and effective compositions and processes for controlling convulsive seizures, and the provision of compositions which are particularly effective against epileptic seizures of the petit mal type. Another object of this invention is the provision of medicaments of the class described which produce few if any side reactions.

An additional object of this invention is to provide I,3,S-trimethyl-s-triazene-2,4,6(lH,3H,5H)-trione in nontoxic dosage form. A further object of this invention is to provide medicaments of the class described which can be administered orally or parenterally.

In accordance with my invention, I have found 1,3,5- trimethyl-s-triazine-2,4,6(lH,3H,5H)-trione to be particularly advantageous in use as an anti-convulsant agent in that little or no side effects are occasioned by ad ministration of this compound. As stated above, it is Well known that other prior art anti-convulsant agents produce photophobia, skin rashes, drowsiness, headache, liver damage, blood dyscrasias, etc. Side reactions of this sort occasioned by use of the above compound occur, if at all, well below a tolerable level. In this regard, the compound has a further advantage of being capable of administration alternately with other anti-convulsant agents, thus minimizing side effects during prolonged treatment with only one anti-convulsant agent.

The 1,3,5 trimethyl-s-triazine-2,4,6( ll-I,3H,5H) -trione, which has been found to possess outstanding anti-convulsant activity, can also be identified as the keto or attain Patented Aug. 18, 1964 lactam form of symmetrical trimethyl isocyanurate, and can be represented by the following formula:

0: N :O I CH This substituted triazine can be prepared by any of a variety of methods. Useful processes include those itemized as follows:

(1) Potassium cyanate can be reacted with potassium methyl sulfate at elevated temperatures.

(2) Cyanuric acid can be reacted with diazomethane.

(3) 2,4,6-trimethoXy-s-triazine can be heated. Advantageous results are observed if this heating takes place in the presence of methyl iodide or the like.

(4) Cyanuric acid can be heated with methyl iodide in the presence of potassium hydroxide or the like.

(5) Silver cyanurate can be reacted with methyl iodide.

(6) Methyl urethane can be heated in the presence of a trace of sodium methoxide.

(7) Cyanuric acid can be reacted with dimethyl sulfate in the presence of aqueous sodium hydroxide or the like.

It will be understood that all suitable processes for the preparation of the compound of Formula 1 may not be exhaustively disclosed herein. Equivalent and other processes suitable for the preparation by batch or continuous process of the compound can be used.

As aforementioned, the compound of Formula 1 is characterized by outstanding anti-convulsant activity. This compound is useful as an effective agent for the control of convulsive seizures, particularly of the epileptic type, as well as other forms of seizures, including certain drug-induced seizure.

One aspect of the invention, therefore, is the novel proces of controlling convulsive seizures which comprises administering to a warm blooded animal afflicted with such seizures a seizure controlling amount of the compound of Formula 1.

The 1,3,5 trimethyl-s-triazine 2,4,6 (1H,3H,5H)- trione compound is administered as a prophylactic agent to effect substantial reduction in the frequency of occurrence and severity of seizures for as long as the medication is continued. The use herein disclosed should not be construed as implying a cure for epilepsy or the complete elimination of epileptic or other convulsive tendencies. This compound can also be used as emergency treatment for seizures.

The process of this invention in the treatment of warm blooded animals is carried out preferably by oral adiminis tration but parenteral administration is also satisfactory. It will be apparent that parenteral administration is sometimes the only possible method of administration for emergency treatment, if swallowing by the recipient is difiicult or impossible and interferes with oral administration.

The seizure controlling amount referred to above, that is to say, the dosage to be administered to the warm blooded animal, will vary under any given conditions,

but in general will depend on the age and weight of the patient, and the magnitude of the effect desired. Thus, as will be understood in the art, larger dosages may be required for emergency treatment.

With reference to administration to a human host subject to seizures, this compound is administered in an amount conveniently calculated on a daily dosage basis, ranging preferably from 50 to 1000 milligrams daily, in single or multiple doses, as the patient requires. If administered orally, the compound .can be given conveniently in 50 or 100 milligram doses at spaced intervals throughout a day. The dosage prescribed for infants and children is generally, but not necessarily, dependent particularly on age and weight, and is generally a somewhat smaller dosage than that for adults. It will be understood that the dosage can also vary depending on other concurrent treatment of the illness. The particular dosage for a given circumstance will readily be selected by persons skilled in the art in accordance with the teachings set forth herein.

The compound of Formula 1, as an anti-convulsant medicament, can be administered alone or in the form of one of the novel compositions of this invention.

According to the present invention, therefore, I have invented useful novel seizure controlling compositions comprising the compound of Formula 1 and a compatible pharmaceutical carrier therefor. I have also invented novel processes for making such compositions. The compositions can be in the form of solutions suitable for injection (of necessity sterile for human consumption) or the compositions can be in the form of articles of manufacture including tablets, capsules, powders, or oral suspensions and syrups. By pharmaceutical carrier in these articles of manufacture, I mean the material present in the article other than the compound of Formula 1. The compatible pharmaceutical carrier can be either solid or liquid material, and can be thereapeutically active or inert. It is of course essential that the carrier is non-toxic.

Usually from about 1 to 95% by weight of the compound of Formula 1 is included in such compositions. The pharmaceutical carrier therefor will constitute usually from about 5 to 99% by Weight of the composition. As will be understood in the art, these ranegs are not critical and can be varied as desired according to attendant circumstances.

As stated above, the novel compositions of this invention can be in the form of solutions suitable for injection which comprise the compound of Formula 1 in a suitable compatible non-toxic solvent.

The preparation of the sterile solution suitable for injection can be accomplished by admixing from about to about 2%, and preferably from 0.5 to 1 /2 by Weight of the compound of Formula 1, and 80 to 99 parts by Weight of Water or isotonic saline at a temperature and for a time sufficient to dissolve the anti-convulsant compound, and sterilizing the solution by filtration or preferably by the application of heat.

The admixing in the preparation of the solution suitable for injection can take place at a temperature from about room temperature to about 120 C. or higher, depending upon the ambient pressure, until solution is complete. Temperatures from 50 to 120 C. are preferred. The temperatures and times depend for example on the amount of active anti-convulsant ingredient present and the physical properties and amounts of the pharmaceutical carrier and its constituents. The admixing can be conveniently accomplished simultaneously with sterilization at a temperature of about 120 C. in an autoclave operating at about p.s.i. steam pressure for from about 5 to 15 minutes. As an alternative to sterilization by the application of heat, sterilization can also be effected by filtration of the solution through a bacterial filter.

In a preferred solution suitable for injection, there is also included a preservative or anti-bacterial agent for the purpose of killing harmful microorganisms or preventing their growth. Useful antibacterial agents include methylparaben in a preferred amount of about 1/ 10%, benzoic acid, and combinations of these. Other non-toxic compatible anti-bacterial agents can be used.

In an exemplary procedure for preparing a solution suitable for injection, the ingredients are admixed, divided into convenient amounts of solution, placed in bottles or the like which are then capped and sealed, and each bottle or the like with its contents then sterilized by the application of heat. For transporting the anti-convulsant solutions, the solution can of course have a relatively high concentration of the active anti-convulsan-t ingredient, and the solution subsequently diluted to a desired concentration before usage.

I have further found that a preferred solution suitable for injection has the following formulation: 1% by weight of the compound of Formula 1, 0.1% methylparaben, U.S.P., as a preservative, approximately 99% distilled water, and sufiicient sodium chloride to make the solution isotonic. One to two daily intravenous injections of about 5 cc. each are suitable for controlling convulsive seizures in an afflicted adult human for extended periods.

In another novel form as an article of manufacture, wherein the anti-convulsant compound is present with a solid pharmaceutical carrier, the carrier can be an ordinary hard or soft gelatin capsule. In this form, the medicament can be administered orally. The capsule can also contain a solid or non-solid, flavored or non-flavored, compatible non-toxic material which can be therapeutically active or inert. Preferred capsule ingredients include solid fillers such as starch, gelatin, lactose, talc, stearic acid, magnesium stearate, and the like. Since the capsules are generally swallowed Whole by the recipient, there is usually no need for flavoring, but such components of the type described below, as well as coloring materials, can advantageously be present. In a preferred capsule article, the compound of Formula 1 is added in an amount of 50 or 100 milligrams to provide a convenient dosage unit form.

In another novel composition according to this invention, the anti-convulsant medicament can be used in the form of a tablet. The tablet is comprised of the active anti-convulsant compound and the carrier which includes a suitable compatible pharmaceutical vehicle, hinder or filler, such as corn starch, acacia, gums, cellulosic materials, as well as the fillers mentioned in the preceding paragraph, and the like. Any of the tableting materials used in pharmaceutical practice can be employed where there is no incompatibility with the active anti-convulsive material.

In an exemplary procedure for making a tablet according to this invention, the several ingredients, which can include suitable lubricants and other adjuvants as will be understood in the art, are compressed, as by a conventional tableting machine, into tablets of preselected size, each containing conveniently the compound of Formula 1 in 50 or 100 milligram dosages. The tablets can be scored if desired so that they can be easily broken in half or other fractional portions. If desired, the tablets can be coated with the conventional tablet coating materials in order to make them more attractive and acceptable to the recipient.

In another novel composition form according to this invention, the anti-convulsant compound of Formula 1 can be prepared and administered in the convenient form of an oral suspension or syrup. This form is particularly suitable for children and infirm persons who have difficulty swallowing a tablet or capsule. The anti-convulsant compound is usually present in such suspensions and syrups in an amount from 1% to 50% by weight, but lower and higher concentrations can advantageously be used.

The pharmaceutical carrier in such suspensions or syrups can be a Watery vehicle such as an aromatic Water, a syrup or a pharmaceutical mucilage.

Suitable aromatic waters include the following:

Anise water, N.F. (IX) Bitter almond water, N.F. (VH1) Camphor water, N.F.

Cinnamon water, U.S.P.

Fennel water, N.F.

Peppermint water, U.S.P. Spearmint water, N.F. (IX) Wintergreen water, N.F. (IX) Suitable syrups include the following:

Suitable pharmaceutical mucilages include the follow ing:

Acacia (gum arabic), U.S.P. Acacia mucilage, U.S.P. Tragacanth, U.S.P. Tragacanth mucilage, NE.

The pharmaceutical carrier in the suspensions or syrups can be a hydroalcoholic vehicle, such as an elixir. Suitable elixirs include the following:

Aromatic elixir, U.S.P.

Red aromatic elixir, N.F. Glycyrrhiza elixir, NF. Iso-alcoholic elixir (iso-elixir), N.F.

Coloring agents, tinctures, spirits, and other adjuvants can be admixed with the composition if desired.

In order that the invention can be better understood, the following examples, in addition to the exemplary illustrations above, are set forth for purposes of illustration:

Example 1 A plurality of unit capsules are prepared by filling standard two-piece hard gelatin capsules weighing about 50 milligrams each with 100 milligrams of powdered 1,3, S-trimethyl s triazine 2,4,6(1H,3H,5H) trione. Convulsive seizures can be controlled for extended periods by 1 to capsules daily taken orally.

Example 2 A plurality of medicinal capsules are prepared by adding in an amount of about 50 milligrams each, powdered compound of Formula 1 to standard soft gelatin capsules, together in each capsule with 50 milligrams of stearic acid. Convulsive seizures can be controlled for extended periods by 1 to capsules daily taken orally.

Example 3 50 milligrams of 1,3,5 trimethyl s triazine-2,4,6(1H, 3H,5H)-trione, 2 /2 milligrams of gelatin, 2 /2 milligrams of magnesium stearate and 100 milligrams of starch are mixed and formed into a tablet by a conventional tableting machine. The tablet is then surface-coated with an artificial cherry-flavored, sweet syrup. Convulsive seizures can be controlled for extended periods by 1 to 20 tablets daily taken orally.

6 Example 4 One hundred parts by weight of the compound of Formula 1, 5 parts by weight of gelatin and 200 parts by weight of starch are admixed until smooth, and the resulting composition screened and compressed into scored tablets, each containing about 50 milligrams of the compound of Formula 1. The tablets are coated with prepared cacao syrup, N.F. Convulsive seizures can be controlled for extended periods by 1 to 20 tablets daily taken orally.

Example 5 A liquid syrup for oral administration is prepared by mixing one part by weight of 1,3,S-trimethyl-s-triazine-Z, 4,6(1H,3H,5H)-trione and 20 parts of raspberry acacia syrup. Convulsive seizures can be controlled for extended periods by l to 15 teaspoonfuls of the mixture daily taken orally.

Example 6 An elfective anti-convulsant oral suspension is prepared by admixing 1 part by weight of the compound of Formula 1, 1 part by weight of acacia, NE, and 98 parts by Weight of water. Convulsive seizures can be controlled for extended periods by 1 to 15 teaspoonfuls of the mixture daily taken orally.

Example 7 Example 6 is repeated except that the mixture additionally contains 5 parts by weight of cocoa syrup, N.F. (V), as a flavoring agent.

Example 8 Example 6 is repeated except that the mixture additionally contains 10 parts by weight of orange syrup as a flavoring agent.

Example 9 A parenteral composition suitable for administration by intravenous injection is prepared by dissolving 1.0 grams of 1,3,5 trimethyl s triazine-2,4,6(1H,3H,5H)- trione in 100 m1. of a sterile aqueous .9% saline solution. Epileptic seizures can be controlled for extended periods by 1 to 2 daily intravenous injections of about 5 cc. each.

Example 10 A solution suitable for injection into humans is prepared by admixing 1.2 g. of the compound of Formula 1, 100 ml. of isotonic saline, and methylparaben, U.S.P. The admixture is sterilized by autoclaving at 15 p.s.i. for 10 minutes.

Example 11 Example 10 is repeated 7 times except that varying amounts of the active anti-convulsant compound is used in quantities of 0.1%, 0.4%, 0.6%, 0.8%, 1.5%, 1.8% and 2.0%.

The compound and compositions of this invention also have utility as laboratory tools in the study of animal behavior, and as control instruments for observing the elfects of drug-induced fits or convulsions in experimental tests. Controlled tests on mice demonstrate the effectiveness of the compound.

The compound of Formula 1 exhibits excellent anticonvulsant activity and is characterized by a more favorable therapeutic ratio than such a known anti-convulsant as trimethadione. Tests have shown the compound of Formula 1 to be approximately 400% more eflfective in controlled testing in comparison with trimethadione.

In addition, the compound and the compositions of this invention are relatively non-toxic, and otherwise not harmful to humans and animals.

This application is a continuation-in-part of my copending application Serial No. 680,627, filed August 27, 1957 (now abandoned), which in turn was a continuation-inpart of my earlier application Serial No. 667,676, filed June 24, 1957 (now abandoned).

I claim:

1. The process of controlling convulsive seizures which comprises administering to a warm blooded animal 1,3,5- trimethyl-s-triazine-2,4,6-( 1H,3H,5H -trione.

2. A process for controlling convulsive seizures which comprises administering to a warm blooded animal a composition containing 1,3,5-trimethyl-s-triazine-2,4,6- (1H,3H,5H)-trione.

3. The process as set forth in claim 1 wherein said administration is orally.

4. The process as set forth in claim 1 wherein said administration is parenterally.

5-. The process of administering to a human subject to seizures from 50 to 1000 milligrams daily of 1,3,5-trimethyl-s-tr-iazine-2,4,6 1H,3H,5 H) -trione.

6. A composition for controlling convulsive seizures comprising an orally acceptable capsule containing a nontoxic coloring agent, a solid filler material selected from the group consisting of starch, gelatin, lactose, talc, stearic acid and magnesium stearate, and from 50 to 100 milligrams of 1,3,5 trimethyl s triazine-2,4,6(1H,3H,5H)- trione.

8 7. An injectable solution comprising to 2% of 1,3,5 trimethyl-s-triazine2,4,6(1H,3H,5H)-trione, from 80 to 99 parts of isotonic saline, and an anti-bacterial agent.

References Cited in the file of this patent UNITED STATES PATENTS Kaiser et al. Jan. 2, 1951 Schaefer et al. Jan. 1, 1952 OTHER REFERENCES 15 nurates, J.A.C.S., volume 73, No. 4, April 10, 1951,

pages 1775-1777.

Close: Anticonvulsant Drugs Isocyanurates, J.A.C.S., volume 75, No. 15, pages 3617-3620 (1953). Scherings Structural Roulette, in Fortune, August 20 1958, volume LVIII, No. 2, pages 102-107, 158, 160, 162,

published by Time, Inc. 

1. THE PROCESS OF CONTROLLING CONVULSIVE SEIZURES WHICH COMPRISES ADMINISTERING TO A WARM BLOODED ANIMAL 1,3.5TRIMETHYL-S-TRIAZINE-2,4,6-(1H,3H,5H)-TRIONE. 